ABSTRACT Formation of misfolded protein oligomers in neurons is an early and causative event in a variety of neurodegenerative diseases, such as Alzheimer?s Disease (?-amyloid and tau oligomers), Fronto-temporal lobe dementia (tau oligomers), and Parkinson?s Disease (?-synuclein oligomers). These toxic oligomers share a common aggregation mechanism that involves formation of hydrogen bonds between individual monomers. A therapeutic that can disaggregate these oligomers, or prevent their formation from monomers, could therefore have extraordinary potential to treat a host of neurodegenerative diseases/disorders. Regarding Alzheimer?s Disease (AD), currently available therapeutics (e.g., AChE inhibitors and memantine) only temporarily slow the rate of cognitive decline without affecting the disease process. This may be in large part because these drugs have not been shown to penetrate the brain?s neurons to disaggregate toxic ?-amyloid (A?) oligomers and tau oligomers therein. The critical importance of addressing the oligomeric forms of A? and tau in AD pathogenesis, along with the failure of many clinical studies using anti-A? aggregating drugs, highlight the need for new, innovative therapies. Since 2007, Dr. Gary Arendash (NeuroEM?s PI) and his collaborators have been developing and testing a new non-pharmacologic intervention against AD ? Transcranial Electromagnetic Treatment (TEMT). In multiple peer-reviewed papers, he has demonstrated in both in vitro and in vivo studies using AD transgenic mice that TEMT prevents and reverses A? oligomerization/aggregation, both inside and outside neurons. These anti-aggregating effects demonstrate that TEMT penetrates the brain parenchyma and neurons to destabilize A? aggregates. The result is a prevention/reversal of cognitive deficits in AD transgenic mice. This proposal?s Aims will focus on administering TEMT through a new prototype head device developed for human TEMT administration against AD. To effectively validate and greatly extend our approach, Aim 1 will utilize assays for oligomeric forms of A?, tau, and ?-synuclein to specifically measure TEMT?s effects on each of these three toxic oligomers in CSF samples placed within a human head mannequin. Aim 2 will then seek to optimize the TEMT parameters for maximum anti-oligomerization and investigate direct mechanisms of TEMT action. The successful execution of these Aims will provide validation of the ?direct? anti-oligomerization effects of TEMT across toxic proteins involved in multiple neurodegenerative diseases. In a follow-up SBIR Fast Track application, NeuroEM will continue this work by: 1) investigating the ?indirect? effects of TEMT in neuronal cell cultures over-expressing these oligomers and 2) performing a Phase II clinical trial involving TEMT administration to AD patients utilizing the optimal set of TEMT parameters. Thus, the extent of both direct and indirect TEMT actions across multiple pathologic oligomers will be determined, as will insight into the anti-oligomerization mechanisms of TEMT action ? all this, utilizing a TEMT head device that we will utilize in a Phase I AD clinical trial starting in Summer 2016 that involves our current set of TEMT parameters.